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In this study, A\u03b2 interactions with the novel two\u2010dimensional (2D) covalent organic frameworks (COFs) as therapeutic options for avoiding \u03b2\u2010amyloid aggregation have been investigated. The results from multi\u2010scale atomistic simulations suggest that amine\u2010functionalized COFs with a large surface area (more than 1000\u2005m<jats:sup>2<\/jats:sup>\/gr) have the potential to prevent A\u03b2 aggregation. Gibb's free energy analysis confirmed that COFs could prevent protofibril self\u2010assembly in addition to inhibiting \u03b2\u2010amyloid aggregation. Additionally, it was observed that the amine functional group and high contact area could improve the inhibitory effect of COFs on A\u03b2 aggregation and enhance the diffusivity of COFs through the blood\u2010brain barrier (BBB). In addition, microsecond coarse\u2010grained (CG) simulations with three hundred amyloids reveal that the presence of COFs creates instability in the structure of amyloids and consequently prevents the fibrillation. 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